WO2015083181A2

WO2015083181A2 - Water soluble pharmaceutical film with enhanced stability

Info

Publication number: WO2015083181A2
Application number: PCT/IN2014/000652
Authority: WO
Inventors: Anwar Siraj DAUD; Nidhi Prakash SAPKAL; Minal Nandkumar BONDE
Original assignee: Zim Laboratories Limited
Priority date: 2013-10-14
Filing date: 2014-10-13
Publication date: 2015-06-11
Also published as: EA201690751A1; CL2016000880A1; UA123893C2; IN2013MU03221A; CA2927334C; WO2015083181A3; CA2927334A1; BR112016008356A2; BR112016008356B1; EA038558B1; MY184297A

Abstract

This invention comprises an Oral Thin Film that is instantly wettable, rapid dissolving, non-sticky, non-tacky and non-curving, the said Film capable of carrying an active ingredient for oral delivery being a moisture stabilized film that remains non-sticky and non-curving when exposed to 70±5 % RH (Relative Humidity) at 25°C for at least 2 minutes up to 2 hours in open conditions without packaging.; and a process/method of making them. The active ingredient may comprise, without limitation, an active pharmaceutical, nutraceutical or cosmaceutical ingredient. The processes/method comprising (a) drying a casted film in two or more stages, (b) drying of the film after casting is done alternately both the sides, (c) coating the dried film with synthetic water insoluble moisture resistant/moisture repellant hydrophobic polymers that does not melt at high temperature, (d) adding a synthetic water insoluble moisture resistant/moisture repellant hydrophobic polymer that does not melt at high temperature to the solution to be casted as a film.

Description

TITLE

WATER SOLUBLE PHARMACEUTICAL FILM WITH ENHANCED STABILITY

TECHNICAL FIELD The present invention relates to orally disintegrating stable film type dosage forms for delivering active pharmaceutical agents, neutraceuticals, diagnostic aids and dietary additives.

BACKGROUND OF THE INVENTION

Oral thin film is a dosage form that is used for delivering various active pharmaceutical active agents, nutraceuticals, diagnostic aids and dietary additives. The mouth dissolving films have been reported for various applications including, without limitation, altering the delivery profile of given pharmaceutical agents, by increasing its rate of dissolution or absorption, or bypassing metabolic processes that increased the bioavailability of the drug. Few illustrative examples are oral thin films disclosed in U.S. patent no. 6709671, U.S. patent application number 2008053466, U.S. patent no. 4900552, and U.S. patent no.5166233.

However, the oral thin films (OTF) available in the market, when exposed to atmospheric conditions for short periods during course of routine use to consume them, undergo curving. The curved edges of OTF pose difficulty in dispensing of these films from multi-dose (Multiple dose) container. These curved edges also pose difficulty in packaging of these films into single or multi-dose packages. These curved edges can lead to dispensing of more than one unit dosage, which is a serious adverse issue related to dose dispensing. Curving of these thin films affects aesthetic appeal and raise doubt about the stability of these films. Hence it is important that films should retain flatness during casting, packaging and throughout their shelf life and should not be deformed during course of conditions of use on account of exposures to variable environmental conditions. Moreover, films prepared by prior methods, have a disadvantage of sticking to each other or to the surface of package because of their smooth surfaces and hygroscopic nature. This leads to limited suitability for the further processing e.g. film cutting, stacking, packaging, dispensing and use and may also lead to microbial contamination, loss in potency and error in dosing.

Further, prior art films involve the use of hydrophilic polymers and use of water in the process of casting the film. Because of these factors, moisture sensitive Active Pharmaceutical Ingredients are not stable during the conventional process of casting these films and during storage.

Thus, OTFs have long unsolved problem of stickiness, curving of the film and instability of moisture sensitive Active Pharmaceutical Ingredients that needed to be solved.

GB927963 achieved prevention of adhering and achievement of non-sticky Water- Soluble Films of Polyvinyl Alcohol Derivatives by making the film from a composition comprising a water-soluble polyvinyl alcohol derivative and not more than 30% by weight of an aliphatic dicarboxylic acid based on the polyvinyl alcohol derivative, the solubility of the said acid being less than 3.0% at 20° C, and more than 0.3% at 100° C. GB927963 also claims a non-sticky film nade from a water soluble polyvinyl alcohol derivative together with less than 30% by weight of an aliphatic di-carboxylic acid, said acid having a solubility in water less than 3.0% at 20° C. and more than 0.3% at 100° C. This method is restricted to the films made specifically from polyvinyl alcohols derivatives and to which an aliphatic dicarboxylic acid has been added, and does not cover within its scope other water soluble polymers and other additives that would result into an a water soluble anti- tacking, non-curving film

US3316190 achieved a cold water soluble polyvinyl alcohol film, which is non- sticky at high humidity comprising either a surface active alone or with water soluble starch as defined in one of the following groups of essential elements: (a) from 0.2% to 20% by weight of a surface active agent having an HLB in the range of 8 to 20, based on the weight of polyvinyl alcohol, (b) from 2% to 50% by weight of a water- soluble starch, based on the weight of polyvinyl alcohol, and from 0.2% to 20% by weight of a surface active agent having an HLB value in the range of 8 to 20%, based on the weight of polyvinyl alcohol, (c) from 2% to 50% by weight of a water- soluble starch, based on the weight of polyvinyl alcohol, and from 0.2% to 20% by weight of an anionic surface active agent having an HLB value in the range of 8 to 20%, based on the weight of polyvinyl alcohol, (d) from 2% to 50% by weight of a water-soluble starch, based on the weight of polyvinyl alcohol, and from 0.2% to 20% by weight of a non-ionic surface active agent having an HLB value in the range of 8 to 20%, based on the weight of polyvinyl alcohol selected from the group consisting of ethylene oxide adducts of fatty acids, fatty alcohols and alkylphenols. Anionic surface active agent used was dialkylsulfosuccinate; and processes of preparing of above embodiments of the films. This patent also describes method of preparation of non sticky films limited to polyvinyl alcohol as film forming polymer and either surface active agent alone or with a surface active agent and water soluble starch.

WO2007030754 discloses films having one of the following groups of essential features/elements of an edible film: (1) at least one anti-tacking agent selected from the group consisting of lubricants, antiadherants, glidants and combinations thereof. (2) an edible, water-soluble polymer component comprising at least one polymer selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyethylene oxide and combinations thereof and an anti-tacking agent comprising Vitamin E TPGS present in amounts of about 0.01% to about 20% by weight of said film, (3) an edible, water-soluble polymer component comprising polyethylene oxide in combination with a polymer selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose and combinations thereof; and Vitamin E TPGS present in amounts sufficient to provide anti-tacking and therapeutic properties, wherein said film is self-supporting, (4) an edible, water-soluble polymer comprising polyethylene oxide and hydroxypropyl cellulose; polydextrose, wherein said polyethylene oxide, hydroxypropyl cellulose and polydextrose are present in a ratio of about 45:45: 10; and at least one anti- tacking agent, (5) an edible, water-soluble polymer; and a coating on said at least one surface of said self-supporting film, said coating comprising at least one anti- tacking agent, (6) a multi-layer film for delivery of an active comprising: (a) at least one first film layer comprising: (i) an edible, water-soluble polymer; and (ii) an anti-tacking agent; and (b) a second film layer comprising: (i) an edible, water-soluble polymer; and (ii) an active component selected from the group consisting of cosmetic agents, pharmaceutical agents, vitamins, bioactive agents and combinations thereof, wherein said first film layer is substantially in contact with said second film layer.

WO2007030754 also discloses a process for making a self-supporting film having a substantially uniform distribution of components comprising following essential features: at least one anti-tacking agent to form a matrix with a uniform distribution of said components; providing a surface having top and bottom sides; (d) feeding said film onto said top side of said surface; and (e) drying said film by applying heat to said bottom side of said surface.

A granted patent from above application WO2007030754, represented by

v

US8765167, has claims narrowed down wherein it claims an oral film for delivery of a desired amount of an active component comprising: an ingestible, water-soluble, polymer matrix, the films having a substantially uniform distribution of said desired amount of said active component within said polymer matrix, which is " measured by substantially equally sized individual unit doses which do not vary by more than 10% of said desired amount of said active component", the film is self-supporting and the active component is substantially uniformly distributed, said film being formed by a controlled drying process which rapidly forms a viscoelastic matrix to lock-in said active in place within said matrix and maintain said substantially uniform distribution; wherein said film is self-supporting and the active component is substantially uniformly distributed. In addition to these elements which are common to all claims, following are some selective essential elements in the claims. In one embodiment (claim 1) the anti-tacking agent to the group is limited to consist of stearates; stearic acid; vegetable oil; waxes; a blend of magnesium stearate and sodium lauryl sulfate; boric acid; surfactants; sodium benzoate; sodium acetate; sodium chloride; DL-Leucine; polyethylene glycol; sodium oleate; sodium lauryl sulfate; magnesium lauryl sulfate; talc; corn starch; amorphous silicon dioxide; syloid; metallic stearates, Vitamin E, Vitamin E TPGS, silica and combinations thereof. In another embodiment (claim 13), the polymers comprise at least one polymer selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyethylene oxide and combinations thereof and an anti-tacking agent is limited to be selected from the group consisting of Vitamin E, Vitamin E TPGS, and sodium benzoate, wherein said anti-tacking agent is present in amounts of about 0.01% to about 20% by weight of said film. In a further embodiment (claim 14), essential elements comprise: an ingestible, water-soluble polymer matrix comprising polyethylene oxide in combination with a polymer selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and combinations thereof; and an anti-tacking agent selected from the group consisting of Vitamin E, Vitamin E TPGS, and sodium benzoate, wherein said anti-tacking agent is present in amounts sufficient to provide anti-tacking and therapeutic properties. In a still further embodiment (claim 15), essential elements comprise: water-soluble polymer matrix comprising polyethylene oxide and a polymer selected from the group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, and carboxymethyl cellulose; and polydextrose, wherein said polyethylene oxide, said polymer selected from the group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, and carboxymethyl cellulose, and said polydextrose are present in a ratio of about 45:45:10 by weight; at least one anti- tacking agent selected from the group consisting of stearates; stearic acid; vegetable oil; waxes; a blend of magnesium stearate and sodium lauryl sulfate; boric acid; surfactants; sodium benzoate; sodium acetate; sodium chloride; DL-Leucine; polyethylene glycol; sodium oleate; sodium lauryl sulfate; magnesium lauryl sulfate; talc; corn starch; amorphous silicon dioxide; syloid; metallic stearates, Vitamin E, Vitamin E TPGS, silica and combinations thereof. In yet another embodiment (claim 16), essential elements are: at least one anti-tacking agent selected from the group consisting of stearates; stearic acid; vegetable oil; waxes; a blend of magnesium stearate and sodium lauryl sulfate; boric acid; surfactants; sodium benzoate; sodium acetate; sodium chloride; DL-Leucine; polyethylene glycol; sodium oleate; sodium lauryl sulfate; magnesium lauryl sulfate; talc; cornstarch; amorphous silicon dioxide; syloid; metallic stearates, Vitamin E, Vitamin E TPGS, silica and combinations thereof. Embodiment represented by Claim 17 discloses a multilayer film comprising: (a) at least one first film layer comprising: (i) an ingestible, water- soluble polymer matrix; and (ii) at least one anti-tacking agent selected from the group consisting of stearates; stearic acid; vegetable oil; waxes; a blend of magnesium stearate and sodium lauryl sulfate; boric acid; surfactants; sodium benzoate; sodium acetate; sodium chloride; DL-Leucine; polyethylene glycol; sodium oleate; sodium lauryl sulfate; magnesium lauryl sulfate; talc; corn starch; amorphous silicon dioxide; syloid; metallic stearates, Vitamin E, Vitamin E TPGS, silica and combinations thereof; and (b) a second film layer comprising: (i) an ingestible, water-soluble polymer matrix; and (ii) a substantially uniform distribution of said desired amount of said active component within said polymer matrix, wherein said active component is selected from the group consisting of cosmetic agents, pharmaceutical agents, vitamins, bioactive agents and combinations thereof, wherein said first film layer is substantially in contact with said second film layer; said film being formed by a controlled drying process which rapidly forms a viscoelastic matrix to lock-in said active in place within said matrix and maintain said substantially uniform distribution. Embodiment of Claim 19 discloses following essential features of a process for making a self-supporting, film comprising: providing a surface having top and bottom sides; feeding the^■ film onto said top side of said surface; and drying said film by applying heat to said bottom side of said surface. Claim 109 essentially claims an embodiment, wherein, in addition to water soluble polymers, use of at least one anti-tacking agent comprising sodium, benzoate, an active component selected from the group consisting of an opiate, opiate derivative, an analgesic and combinations thereof; said film being formed by a controlled drying process to maintain a substantially uniform distribution thereof. Claim 1 10 has disclosed following essential elements: a multi-layer film comprising: (a) a first film layer comprising: (i) an ingestible, water-soluble or water-swellable polymer matrix; and (b) at least a second film layer comprising: (i) an ingestible, water-soluble or water-swellable polymer matrix comprising a water-soluble or swellable polymer; wherein the first and/or second layers further comprise: a desired amount of a substantially uniformly distributed active component, a component selected from the group consisting of an anti-tacking agent, a sweetener, a flavor, an acidulent, an oxide filler, propylene glycol, vitamin E acetate, polyacrylic acid, a preservative, a buffer, a coloring agent and combinations thereof; and wherein said first film layer is substantially in contact with said second film layer; said film being formed by a controlled drying process to maintain substantially uniform distribution of the component. In the context of above patent, Vitamin E is an oily liquid. Its presence in the film beyond a certain concentration will make the film appear oily and hamper with its aesthetic appeal. Moreover, all the film formulations require addition of suitable plasticizers which at many instances are liquids. Addition of vitamin E along with liquid plasticizers will result into films that are oily to touch. That means using vitamin E and other liquid excipients to make film non sticky will pose a restriction to the use of other liquid or oily excipients that are used for other functions like, plasticizers, flavors, surfactants, emulsifiers, sweetener, etc.

However, use of vegetable oils and waxes including strearic acid impart unacceptable taste to the film when it is meant to get dissolved in oral cavity. Being liquid at higher ambient temperatures the waxes alter the appearance of films by making them appear waxy. Vegetable oils have problems of oxidation and rancidity and thus will require the incorporation of antioxidants. Further some of the excipients mentioned as anti-tacking agents belong to the class of lubricants but when used in the films give sticky films because of their oily and waxy nature like strearic acid, vitamin E, oils and waxes. Similarly amongst the mentioned excipients some are hygroscopic in nature e.g. polyethylene glycols, boric acid etc. Films made using these hygroscopic excipients will be sensitive to atmospheric conditions and will not be stable for a sufficiently long time.

Further, the above mentioned application does not describe details of the controlled heating process. During the casting of such films, the films are always casted on a support material which may be made up of PVC or similar materials, stainless steel belt or some other metal bets. While heating is being done from the bottom side the heat will be first transferred to the support material which in turn will pass to the film. The way a film gets dried will be affected by the nature of the support material. It is desired to achieve non-sticky films by methods other than used so far so that a wider choice of methods is available to make non-sticky films, which may require different methods for different requirements of actives that are added to the film.

Further, despite non-sticky nature, the methods disclosed in the prior art do not make films that are free from problem of curving.

Accordingly, it is an object of present invention to provide orally disintegrating stable film dosage form for delivering active pharmaceutical agents, neutraceuticals, dietary additives, diagnostic aids and cosmaceuticals by alternative newer methods. Another objective of present invention is to solve the problem of curving in the film, from the edges when exposed to atmospheric conditions of varying humidity and temperature. Prior art talks only about the stability of films and is silent on the curving problem of the film. But the films available in the market have this problem. Yet another objective of present invention is to provide instant wettability, adequate tensile strength and fast disintegration while achieving stable films that are non- curving and non sticky or non tacky by newer methods.

Yet another objective of present invention is to provide manufacturing techniques and methodologies for manufacturing of non-curving, and non-sticky films.

For the purpose of this specification, the term "stable film" means and includes "non-curving film" and "non-sticky or non-tacky film".

SUMMARY OF THE INVENTION

This invention comprises an Oral Thin Film that is instantly wettable, rapid dissolving, non-sticky, non-tacky and non-curving, the said Film capable of carrying an active ingredient for oral delivery being a moisture stabilized film that remains non-sticky and non-curving when exposed to 70±5 % RH (Relative Humidity) at 25°C for at least 2 minutes up to 2 hours in open conditions without packaging. This invention also comprises processes/methods to make the said Oral Thin Film that is instantly wettable, rapid dissolving, non-sticky, non-tacky and non-curving. In one embodiment, the process/method of preparation of the said rapidly dissolving oral water soluble film for oral delivery of an active ingredient comprises steps of casting a film comprising water soluble polymer/s, optional additives; and drying the same by application of heat; wherein the drying of the film after casting is done by increasing temperature of drying in two or more stages. In one embodiment of this process/method in the first stage the temperature of drying is kept in a range of 45°C to 60°C and drying is done until the moisture content of the film reaches in the range of 50% to 20%, in the second stage, temperature is kept in the range of 60°C to 110°C and drying is done until the moisture content of the film reaches in the range of 30 % to 10 %, and in the third stage, temperature is kept in the range of 80°C to 130°C and drying is done until the moisture content of the film reaches to in the range of 10% to 2% at the end of drying process. The process of this embodiment also comprises addition of additives, which comprise an active ingredient and excipients. The active ingredient may comprise, without limitation, an active pharmaceutical, nutraceutical or cosmaceutical ingredient.

In another embodiment, this invention comprises a process/method of preparation of the said rapidly dissolving oral water soluble film for oral delivery of an active ingredient, the process comprising steps of casting a film comprising water soluble polymer/s, optional additives; and drying the same by application of heat; wherein the drying of the film after casting is done alternately on both the sides wherein: (a) in the first stage, drying is done on top side of the casted film at 70° C to 120° C until moisture content of the film reaches in the range of 50% to 20%, (b) the resulting film is then removed from the support and dried in second stage from other side at 70 0 to 120° C until the moisture content reaches in the range of 20% to 2%. Preferably, the first stage drying is preferably done in the range 35% to 25% and the second stage drying is done in the range of 10% to 2%, and the film contains an active ingredient. This process/method may comprising following steps: (a) casting a solution comprising a rapidly water soluble polymer as a film on a support, (b) drying the casted film at 100° C to a semi -dried condition to a moisture content in the range of 20% to 50%, (c) coating the semi-dried film with moisture resistant or moisture repellent solution, (d) drying at 80° C, (e) removing the double layer film from the support, (f) flipping the removed double layer film and further casting with , moisture resistant or moisture repellant solution, and (g) drying at 80° C. The thickness of the thin film of the moisture resistant or moisture repellent polymer may be in the range of 1-5 μιη, the thickness of the entire single layer or multilayer film may range from 40 μπι to 150 μπι, and moisture of the entire film may range from 10% to 2%.

In yet another embodiment, this invention comprises a process/method of preparation of a said rapidly dissolving oral water soluble film for oral delivery of an active ingredient comprising steps of casting a film comprising water soluble polymer/s, optional additives; and drying the same by application of heat, coating the dried film with synthetic water insoluble moisture resistant/moisture repellant hydrophobic polymers that does not melt at high temperature; wherein the thickness of the coating being such that it prevents uptake of moisture from ambient humidity, but dissolves rapidly when contacted with water.

In yet another embodiment, this invention comprises a process/method of preparation of the said rapidly dissolving oral water soluble film for oral delivery of an active ingredient comprising steps of casting a film comprising water soluble polymer/s, optional synthetic water insoluble moisture resistant/moisture repellant additives and one or more of a synthetic water insoluble moisture resistant/moisture repellant hydrophobic polymer that does not melt at high temperature, wherein the said polymer is added in a range that shall permit instant wettability arid rapid dissolution when the film comes in contact with water. The synthetic water insoluble moisture resistant moisture repellant hydrophobic polymer used in the film is in a concentration range from 1.5% to 7.5% of the dry weight of the dry film. The water insoluble polymer, preferably, is polymethacrylate. This process/method may further comprise, in addition to water insoluble polymer, addition of one or more of moisture absorbents also to make the film.

DETAILED DESCRIPTION

Brief description of figures and legends

Figure 1 : The diagram of machine used to manufacture the stabilized film (1) denotes casting solution/dispersion (2) Roller, (3) First stage drying, (4) Casted Film , (5) Support roller, (6) Second stage drying.

Figure 2: - Depicts the diagram of machine used to manufacture the moisture repellent/ moisture resistant film. (1) denotes casting solution/dispersion, (2) Roller, (3) film casting, (4) Heater, (5) Moisture resistant polymeric solution, (6) Heater, (7) Flipping of film, (8) Moisture resistant polymeric solution, (9) Heater, (10) dried film.

Figure 3: depicts (1) a Multiple dose container, (2) films stacked in the multiple dose container, and (3) dispensing of one film from the stack, which exposes the films to ambient humidity in the course of handling and makes dispensing difficult if the films are sticky or/and curved.

The present invention comprises a method of manufacturing of instantly wettable, non-sticky and non-curving OTF by using means of improving moisture stabilization ' of the OTF at an ambient humidity at or below 70±5 % RH; wherein moisture stabilization is defined as retention of flatness of the thin film during casting, packaging and storage such that the OTF remains non-sticky and non-curving when exposed to 70±5 % RH (Relative Humidity) at 25°C for at least 2 minutes up to 2 hours in open conditions without packaging..

The invention also provides an instantly wettable, oral dissolving, non-sticky and non-curving Oral Thin Film capable of carrying an active ingredient for oral delivery and a method of manufacturing of the same.

In first embodiment of the means of improving moisture stabilization of the OTF, a casted film is dried at gradually increasing temperature. In an illustrative embodiment, the temperature is increased in three stages. In the first stage the temperature is kept in a range of 45°C to 60°C and drying is done until the moisture content of the film reaches in the range of 50% to 20%; in the second stage, temperature is kept in the range of 60°C to 1 10°C and drying is done until the moisture content of the film reaches in the range of 30 % to 10' %; and in third stage, temperature is kept in the range of 80°C to 130°C and drying is done until the moisture content of the film reaches to in the range of 10% to 2% at the end of drying process (Example 1).

In second embodiment of this invention, moisture stabilization of the OTF is achieved by drying of a casted film alternately on both the sides in two stages. In the first stage, drying is done on top side of the casted film at 100° C until moisture content of the film reaches in the range of 50% to 20%, more preferably in the range 35% to 25%. The resulting film is then removed from the support and dried from other side at 100° C until the moisture content reaches in the range of 20% to 2%, more preferable in the range of 10% to 2%. Figure 1 depicts the diagram of machine used to manufacture the stabilized film (Example 2).

The First and Second embodiment of this invention described above are improvement over prior art methods of drying of casted films. The prior art methods comprise drying of casted films on one side of the films by exposing to heat, which leads to migration of all water soluble constituents from one side along with water molecules, this is one of the reasons for defects in the film like curving of edges, sticking etc. or to make a uniform film, they are required to make rapid heating, but they do not result into a non-curving film because the heating/drying is uneven at two surfaces. In the instant invention, (a) the heating, when dome on One side only, is done in more than two stages giving reasonable time for the moisture to get readjusted, come to an equilibrium across the cross section of the film and then further drying is done in further stage; or (b) it is done in two stages, in first stage on one side upto a certain temperature, and then it is flipped and further drying at higher temperature is done on the other side; these two approaches result in a film that not only results in a uniform molecular distribution but also results in a uniformly dried film that is non-curving also.

Figure 2 depicts the diagram of machine used to manufacture the moisture repellent/ moisture resistant film.

In third illustrative embodiment, this invention comprises moisture stabilization of an OTF made from water soluble polymers by coating them with water insoluble moisture resistant/moisture repellant, hydrophobic polymers that does not melt at high temperature and alter/s the ability of films to absorb moisture and make them resistant to changing ambient humidity conditions to overcome stickiness and curving of the film during storage and usage; wherein the thickness of the coating being such that it prevents uptake of moisture from ambient humidity, but dissolves rapidly when contacted with water. The said moisture resistant/ repellent polymers are used as a thin layer on the already casted oral thin film coating or enveloping the film from both the sides using thin layer of moisture resistant/ moisture repellent agents. This results in enveloping of film for its protection from moisture. The resulting film remains flat and flexible. A preferred range of thickness of coated layer is in the range of 5-1 μιη. In this embodiment, in the first stage, solution casting and drying is done at 100 °C, the semidried film possesses moisture in the range of 20% to 5%. The resulting film is then coated/ casted with moisture resistant/ moisture repellent polymeric solution and dried at 80° C. The resulting double layered film is removed from the support; flipped and further casting is done with moisture resistant/ moisture repellent solution and dried at 80° C. The resulting tripled layered/ laminated film contains moisture in the range of 10% to 2%. This invention is illustrated by Examples 3, 3.1 and 3.2. The said moisture resistant/ repellent polymers are used as a thin layer on the already casted oral thin film may be polyacrylates.

In fourth embodiment of this invention moisture stabilization was achieved by adding, to the water soluble polymer containing solution prepared for casting the film, a synthetic water insoluble hydrophobic polymer that does not melt at even extreme temperature conditions such as 55 to 60 °C, the said synthetic polymer being added in a range that shall not adversely affect the dissolution property of the film, shall permit instant wettability and rapid dissolution when the film comes in contact, with water but shall impart non folding, non curving and non sticky characteristic to the films. Such water insoluble polymers include, without limitation, Acrylic/methacrylic acid copolymers including pH dependent polymers such as acrylic acid/methacrylic acid copolymers, pH . independent polymers including acrylic/methacrylate copolymers and carbomer polymers. Presence of hydrophobic/water-insoluble polymer in concentration range from 1.5 to 7.5 % in the conventional composition of films will impart non curving and nort sticky characteristic to the films (Example 4).

In a fifth embodiment of means of improving moisture stabilization of the OTF, moisture adsorbants and hydrophobic polymers can be added in combination in the range of 1 to 10 %.

Other components like emulsifying agents, preservatives, buffering agents, antioxidants, plasticizers, super-disintegrants, absorbents, sweeteners, taste modifiers, flavorants, colorants, water insoluble polymers, pH modifiers, buffering agents, surfactants and stabilizers may also be added while making an Oral Thin Film. The film forming polymer that can be used for making films of this invention comprise one or more or a combination of hydrocolloids, natural or semi synthetical, and comprising, without limitation, hydroxypropyl methyl cellulose, hydroxy ethyl cellulose, carboxy methyl cellulose, pullulan, polyvinyl alcohol, polyethylene glycol graft polymer, soluble cellulosic polymers, guar gum, xanthan gum, locust bean gum, carrageenan, gum tragacanth, pectin, Carboxy methyl guar gum, and Carboxy methyl locust bean gum. The Polyoxyethylene polymers are selected according to the viscosity and the molecular weight. ^ The preferred ranges in which various ingredients used are indicated below in percentages of dry weight of the final film comprising, without limitation: active agentsO.01 -80%, emulsifying agent/s 0.1 %- 10%, preservative/s 0.01-10%, buffering agent/s 0.01-10%, antioxidant/s 0.001-10%, plasticizer/s 0.5-40%, super dis- integrant/s 0.01 to 5%, absorbent/s 0.01 to 10 %, flavoring agent/s 0.001-10%, coloring agent/s 0.001-5%, water-insoluble/hydrophobic polymer/s 1.5 to 7.5 %, pH modifier/s 0.01-10%, buffering agent/s 0.01 to 5 %, stabilizer/s 0.01-5% and water soluble polymer/s 25 - 85%.

Moisture resistant polymers used in this invention comprise, without limitation, polymethacrylate/s. The polymethcryalte used may be selected form the group comprising, without limitation: Poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate), Poly(ethyl acrylate, methyl methacrylate), Poly(methacrylic acid, methyl methacrylate), Poly(methacrylic acid, ethyl acrylate), Poly(methacrylic acid, methyl methacrylate), Poly(methyl acrylate, methyl methacrylate, methacrylic acid), Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) ethyl cellulose, phthalate derivatives and shellac.

Thickness of the single or multi-layer films may vary widely in the range of 40 μηι to 150 μπι, more preferably from about 50 μηι to about 120 μπι and has the moisture content in the range of 10% to 2%.

The above list is illustrative only and does not have any limiting effect; the illustrated ingredients can be replaced by alternative substances having equivalent function and properties which are known to those skilled in the art.

The active compound/ingredient may, for example, be medicinal, neutraceutical, dietary additive, cosmaceutical, colorant and a dignostic.

This invention is especially suitable for pharmaceutical, neutraceutical and dietary additives that have ability to absorb moisture or those that degrade in the presence of moisture.

Besides above mentioned embodiments, there may be several other embodiments that achieve moisture stabilization, including the ones which are obvious variants of above or equivalents of above, and all of them are included within the scope of disclosure of this specification. The non-limiting examples given below are only illustrative and do not limit the scope of means used for moisture stabilization nor the conditions used for moisture stabilization.

Example 1

Drying a casted film at gradually increasing temperature

Maltodextrin 15.6

Polyvinyl alcohol 1.8

Sorbic Acid 0.2

Sucralose 0.4

Polysorbate 80 2

Water 80

Maltodextrin, polyvinyl alcohol, bronopol, sucralose and Polysorbate 80 were added in order as they appeared in table 1 in 400 ml of water. The resulting solution was then stirred at room temperature until homogeneous solution was formed. It was then coated onto a belt of support material using conventional coating equipment. Support material could be Teflon coated PVC, simple PVC or Stainless steel belt. Wet film thickness was adjusted to achieve dry thickness between 20 to 50 μηι. Resulting film was then dried in first heating chamber at 60°C, the film was then allowed to cool to room temperature and then re-dry at 90°C in second drying chamber, resulting film was again allowed to cool to room temperature and again this procedure was repeated for drying of film in third heating chamber at 120°C. The resulting film was then removed from support and cut into pieces of desired size and shape. The formed films were uniform in appearance and dissolved rapidly.

Moisture stability test: These films were then packed in multi-dose containers that were not air tight and exposed to 70±5%, 50±5% and 30±5% RH (relative humidity) at a temperature of 25±2°C and were observed for 15, 30 and 45 min for their stability in exposed and packed conditions. Films were stable for 10, 12 and 15 minutes respectively in exposed conditions and in a condition when a multi-dose container in which these films are placed, after they are exposed in course of handling for use to ambient humidity for a multiple number of times for a total of 45 minutes of exposure. Example 1.1:

Drying a casted film containing pharmaceutical agent at gradually increasing temperature

Phenylephrine, maltodextrin, polyvinyl alcohol, bronopol, sucralose and Polysorbate 80 were added in order as they appeared in table 1 in 400 ml of water. The resulting solution was then stirred at room temperature until homogeneous solution was formed. It was then coated onto a belt of support material using conventional coating equipment. Support material could be Teflon coated PVC, simple PVC or Stainless steel belt. Wet film thickness was adjusted to achieve dry thickness between 20 to 50 μηι. Resulting film was then dried in first heating chamber at 60°C, the film was then allowed to cool to room temperature and then re-dry at 90°C in second drying chamber, resulting film was again allowed to cool to room temperature and again this procedure was repeated for drying of film in third heating chamber at 120°C. The resulting film was then removed from support and cut into pieces of desired size and shape. The formed films were uniform in appearance and dissolved rapidly. These films were then packed in multi-dose containers and exposed to 70±5%, 50±5% and 30±5% RH (relative humidity) at a temperature of 25±2°C and were observed for 15, 30 and 45 min for their stability in exposed and packed conditions. Films were stable for at least 10, 12 and 15 minutes respectively in exposed conditions and in multi-dose container in which these films are placed, after they are exposed in course of handling in course of use to ambient humidity for a multiple number of times for a total of 45 minutes of exposure .

Example 1.2:

Formulating stable film containing pharmaceutical active agent dried using gradually increasing temperature.

HPMC was dissolved in fixed quantity of water and PEG 4000 was added to HPMC solution. Remaining ingredients including phenylephrine were added to polymeric solution. The resulting solution was then stirred at room temperature until homogeneous solution was formed. It was then coated onto a belt of support material using conventional coating equipment. Support material could be Teflon coated PVC, simple PVC or Stainless steel belt. Wet film thickness was adjusted to achieve dry thickness between 20 to 50 μπι. Resulting film was then dried in first heating chamber at 60°C, the film was then allowed to cool to room temperature and then re-dry at 90°C in second drying chamber, resulting film was again allowed to cool to room temperature and again this procedure was repeated for drying of film in third heating chamber at 120°C. The resulting film was then removed from support and cut into pieces of desired size and shape. These films were then packed in multi-dose containers and exposed to different humidity conditionsas described in example 1 and were observed for 15, 30 and 45 min for their stability in exposed and packed conditions. Films were stable for at least 10, 12 and 15 minutes respectively in exposed conditions and in multi-dose container in which these films are placed, after they are exposed in course of handling in course of use to ambient humidity for a multiple number of times for a total of 45 minutes of exposure . Example 2

Drying the film in two stages

Name of excipients Amount (In %)

Pullulan 14.54

Polyvinyl alcohol 1.79

Bronopol 0.20

Sucralose 0.40

Polysorbate 80 1.99

Polyethylene Glycol 1.40

Water 79.68 Pullulan, polyvinyl alcohol, bronopol, sucralose and Polysorbate 80, talcum and titanium dioxide were added in 400 ml water in the fashion presented in the Example 1. The resulting solution was then stirred at room temperature until homogeneous solution was formed. It was then coated onto a belt of support material Support material could be Teflon coated PVC, simple PVC or Stainless steel belt using conventional film casting equipment. Wet film thickness was adjusted to achieve dry thickness between 20 to 50 μιη. In first stage, drying was done from top at 100°C. The resulting film was then removed from support and dried from other side at 100°C. The resulting films was then removed from support and cut into pieces of desired size and shape. The so prepared films were then subjected to the test described in example 1 and it was found that all the films retained their flatness for at least up to 10 minutes in exposed conditions and throughout the observation period in packed conditions.

Example 2.1:

Simethicone and Neusilin were mixed intimately and were added to the solution of Pullulan, polyvinyl alcohol, bronopol, sucralose and Polysorbate 80, in fixed quantity of water. The resulting solution was then stirred at room temperature until homogeneous solution was formed. It was then coated onto a belt of support material. Support material could be Teflon coated PVC, simple PVC or Stainless steel belt using conventional film casting equipment. Wet film thickness was adjusted to achieve dry thickness between 20 to 80 μιη. In first stage, drying was done from top at 100°C. The resulting film was then removed from support and dried from other side at 100°C. The resulting films were then removed from support and cut into pieces of desired size and shape.

The so prepared films were then subjected to the test described in example 1 and it was found that all the films retained their flatness for at least upto 10 minutes in exposed conditions and throughout the observation period in packed conditions.

Example 2.2: Drying of film containing pharmaceutical agent in two stages.

Name of Ingredients Quantity in

percentage

Simethicone 20

Neusilin 8

HPMC 5 cps 20

PVA 5

Polyethylene Glycol 3.5

Tween 80 1.45

Sucralose 0.05 Water 42

Simethicone and Neusilin were mixed- intimately and were added to the solution of HPMC, polyvinyl alcohol, Polyethylene Glycol, sucralose and Tween 80 in fixed quantity of water. The resulting solution was then stirred at room temperature until homogeneous solution was formed. It was then coated onto a belt of support material Support material could be Teflon coated PVC, simple PVC or Stainless steel belt using conventional film casting equipment. Wet film thickness was adjusted to achieve dry thickness between 20 to 80 μπι. In first stage, drying was done from top at 100°C. The resulting film was then removed from support and dried from other side at 100°C. The resulting films were then removed from support and cut into pieces of desired size and shape.

The so prepared films were then subjected to the test described in example 1 and it was found that all the films retained their flatness for at least upto 12 minutes in exposed conditions and throughout the observation period in packed conditions. Example 3

Method of making non-sticky oral thin films by using coating or enveloping the film

Name of excipients Amount (In %)

Solution A

Pullulan 13. 44

Polyvinyl alcohol 1.99

Bronopol 0.20

Sucralose 0.40

Polysorbate 80 1.99

Water 67.00

Solution B Methycrylic acid 2.3

copolymer

Ethanol 12.68

Solution A; Pullulan, Polyvinyl alcohol,Bronopol, Sucralose and Polysorbate 80 were added in water.

Solution B; methycrylic acid copolymer was dissolved in ethanol. Solution A was stirred at room temperature until homogeneous solution was formed. Wet film thickness was adjusted to achieve dry thickness between 20 to 50 μιη. Drying was done at 100°C. Then solution B was coated on moisture resistant/ moisture repellent polymeric solution and dried at 80°C. The resulting double layered film is removed from the support; flipped and further casting is done with moisture resistant/ moisture repellent solution and dried at 80°C. The resulting tripled layered/ laminated film contains moisture in the range of 10% to 2%.

The so prepared films were then subjected to the test described in example 1 and it was found that all the films retained their flatness for at least upto 10 minutes in exposed conditions and throughout the observation period in packed conditions. Example 3.1

Method of making stable films by coating both sides of films

Bronopol 0.189

Polysorbate 80 0.37 ·

Sucralose 1.86

Water ^' 82

Solution A: Donepezil, Pullulan, Polyvinyl alcohol, Bronopol, Sucralose and

Polysorbate 80 were added in water.

Solution B: As described in example 3

Solution A was stirred at room temperature until homogeneous solution was formed. Wet film thickness was adjusted to achieve dry thickness between 20 to 50 μιη. Drying was done at 100°C. Then solution B was coated on moisture resistant/ moisture repellent polymeric solution and dried at 80°C. The resulting double layered film is removed from the support; flipped and further casting is done with moisture resistant/ moisture repellent solution and dried at 80°C. The resulting tripled layered laminated film contains moisture in the range of 10% to 2%.

Example 4

Coating moisture sensitive ingredient particles with moisture resistant polymers

Glycerin 4.20

Sucralose 0.40

Polysorbate 80 1.99

Talcum 0.20

Titanium dioxide 0.20

Water ^; 72.68

Particles of Montelukast sodium were coated with methacrylate acid copolymer using fluidized bed coater. Pullulan, polyvinyl alcohol, bronopol, sucralose and Polysorbate 80, talcum and titanium dioxide, were added in 400 ml water in the order presented in the Example 1. The resulting solution was then stirred at room temperature until homogeneous solution was formed. Resulting solution was then coated onto a belt of support material using conventional film casting equipment Support material could be Teflon coated PVC, simple PVC or Stainless steel belt. Coating thickness was adjusted to achieve dry thickness between 20 to 50 μιη. Resulting film was then dried in heating chamber at 120°C. The resulting film was then removed from support and cut into pieces of desired size and shape.

The so prepared films were then subjected to the test described in example 1 and it was found that all the films retained their flatness for at least upto 10 minutes in exposed conditions and throughout the observation period in packed conditions. Example 5:

Formulation of stable films using hydrophobic polymers

Name of Ingredients Quantity in percent

Ondansetron 4.4 Methacrylate acid copolymer 3.3

HPMC 22.2

Polyvinyl alcohol 2.77

Glycerin 5.55

Sucralose 0.55

Polysorbate 80 1.11

Water 60

Polymeric solution was prepared by adding HPMC to the fixed quantity of water and remaining ingredients were added to this solution. The solution was mixed to obtain the homogenous dispersion and casted on a support to obtain a dry film with thickness in the range of 50 to 100 μτη. The film was dried at 70°C to obtain moisture content in the range of 4% to 10%. The resulting film was then removed from support and cut into pieces of desired size and shape.

Example 6:

Name of Ingredients Quantity (In %)

Ondansetron 3.69

Methacrylate acid 2.77

copolymer

HPMC 18.66

Polyvinyl alcohol 2.32

Glycerin 4.66 Sucralose 0.46

Polysorbate 80 0.93

Talcum 3.69

Titanium dioxide 2.77

Water 60

Polymeric solution was prepared by adding HPMC to the fixed quantity of water and remaining ingredients were added to this solution. The solution was mixed to obtain the homogenous dispersion and casted on a support to obtain a dry film with thickness in the range of 50 to 100 μηι. The film was dried to obtain moisture content in the range of 4% to 10%. The resulting film was then removed from support and cut into pieces of desired size and shape. The so prepared films were then subjected to the test described in example 1 and it was found that all the films retained their flatness for at least upto 15 minutes in exposed conditions and throughout the observation period in packed conditions.

Claims

1. A process/method of preparation of a rapidly dissolving oral water soluble film for oral delivery of an active ingredient, the process comprising steps of casting a film comprising water soluble polymer/s, optional additives; and drying the same by application of heat; wherein the drying of the film after casting is done by increasing temperature of drying in two or more stages, the process/method resulting into a moisture stabilized film that remains non-sticky and non-curving when exposed to 70±5 % RH (Relative Humidity) at 25°C for at least 2 minutes up to 2 hours in open conditions without packaging.

2. The process/method of claim 1 wherein the drying is done in three stages, wherein:

a. in the first stage the temperature of drying is kept in a range of 45°C to 60°C and drying is done until the moisture content of the film reaches in the range of 50% to 20%;

b. in the second stage, temperature is kept in the range of 60°C to 110°C and drying is done until the moisture content of the film reaches in the range of 30 % to 10 %; and

c. in third stage, temperature is kept in the range of 80°C to 130°C and drying is done until the moisture content of the film reaches to in the range of 10% to_, 2% at the end of drying process, and

d. additives comprise an active ingredient and excipients

3. A process/method of preparation of a rapidly dissolving oral water soluble film for oral delivery of an active ingredient, the process comprising steps of casting a film comprising water soluble polymer/s, optional additives; and drying the same by application of heat; wherein the drying of the film after casting is done alternately on both the sides in two stages, wherein: (a) in the first stage, drying is done on top side of the casted film at 70° C to 120° C until moisture content of the film reaches in the range Of 50% to 20%, and (b) in the second stage, the resulting film is then removed from the support and dried from other side at 70 ⁰ to 120° C until the moisture content reaches in the range of 20% to 2%; the process/method resulting into a moisture stabilized film that remains non-sticky and non-curving when exposed to 70±5 % RH (Relative Humidity) at 25°C for at least 2 minutes up to 2 hours in open conditions without packaging.

4. The process/method of claim 3 wherein:

a. the first stage drying is done in the range 35% to 25%. or

b. the second stage drying is done in the range of 10% to 2%, orthe first stage drying is done in the range 35% to 25% and the second stage drying is done in the range of 10% to 2%.

5. The process/method of claim 2 or claim 4 wherein the film contains an active ingredient.

6. The process/method of claim 5 wherein the active ingredient is an active pharmaceutical, nutraceutical or cosmaceutical ingredient.

7. A process/method of preparation of a rapidly dissolving oral water soluble film for oral delivery of an active ingredient comprising steps of casting a film comprising water soluble polymer/s, optional additives; and drying the same by application of heat, coating the dried film with synthetic water insoluble moisture resistant/moisture repellant hydrophobic polymers that does not melt at high temperature; wherein the thickness of the coating being such that it prevents uptake of moisture from ambient humidity, but dissolves rapidly when contacted with water; the process/method resulting into a moisture stabilized film that remains non-sticky and non-curving when exposed to 70±5 % RH (Relative Humidity) at 25°C for at least 2 minutes up to 2 hours in open conditions without packaging.

8. A process/method of preparation of a rapidly dissolving oral water soluble film for oral delivery of an active ingredient comprising steps of casting a film comprising water soluble polymer/s, optional synthetic water insoluble moisture resistant/moisture repellant additives and one or more of a synthetic water insoluble moisture resistant/moisture repellant hydrophobic polymer that does not melt at high temperature, wherein the said polymer is added in a range that shall permit instant wettability and rapid dissolution when the film comes in contact with water; the process/method resulting into a moisture stabilized film that remains non-sticky and non-curving when exposed to 70±5 % RH (Relative Humidity) at 25°C for at least 2 minutes up to 2 hours in open conditions without packaging.

9. The process/method of claim 7 or claim 8 wherein the synthetic water insoluble moisture resistant/moisture repellant hydrophobic polymer is used in the film is in a concentration range from 1.5% to 7.5% of the dry weight of the dry film.

10. The process/method of claim 8 or claim 9 wherein the water insoluble polymer is polymethacrylate.

11. The process/method of claim 10 wherein the polymethacrylate consists of one or more selected from the group Poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate), Poly(ethyl acrylate, methyl methacrylate), Poly(methacrylic acid, methyl methacrylate), Poly(methacrylic acid, ethyl acrylate), Poly(methacrylic acid, methyl methacrylate), Poly(methyl acrylate, methyl methacrylate, methacrylic acid), Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) ethyl cellulose, phfhalate derivatives and shellac.

12. The process/method of claim 8 further comprising addition of water insoluble polymer and one or more of moisture absorbents to make the film.

13. The process/method of claim 7 further comprising following steps:

a. casting a solution comprising a rapidly water soluble polymer as a film on a support,

b. drying the casted film at 100° C to a semi-dried condition to a moisture content in the range of 20% to 50%,

c. coating the semi-dried film with moisture resistant or moisture repellent solution, and

d. drying at 80° C,

e. removing the double layer film from the support,

f. flipping the removed double layer film and further casting with moisture resistant or moisture repellant solution, and

g. drying at 80° C.

14. The process/method of claim 7 wherein:

a. the thickness of the thin film of the moisture resistant or moisture repellent polymer is in the range of 1-5 μηι,

b. the thickness of the entire single layer or multilayer film ranges from 40 um to 150 μηι, and

c. moisture of the entire film ranges from 10% to 2%.

15. An Oral Thin Film that is instantly wettable, rapid dissolving, non-sticky, non-tacky and non-curving, the said Film capable of carrying an active ingredient for oral delivery being moisture stabilized, remains non-sticky and non-curving when exposed to 70±5 % RH (Relative Humidity) at 25°C for at least 2 minutes up to 2 hours in open conditions without packaging.